Chronic orofacial pain, major clinical problem causing significant morbidity and societal economic impact is presently treated with limited success in large part due to inadequate understanding of the underlying pain mechanisms. The theme of this program project is to elucidate cellular mechanisms involved in nociceptive transmission relevant to trigeminal pain. A highly interactive and cohesive group effort will be based on the continuing active collaboration among the present principal investigators who will continue to provide each other complementary knowledge, conduct formal research conferences together, and share equipment and techniques, especially those related to molecular anatomy. Drs. David Julius and Allan Basbaum, in a joint project employing behavioral, anatomical and electrophysiological experiments in knockout mice will evaluate the primary afferent nociceptive function of the two vallinoid receptors that were that were cloned during the current grant period. These studies should provide important information on thermal and cloned during the grant period. These studies should provide important information on thermal and chemical nociceptive transduction. Dr. Marc Tessier-Lavigne will use genomic approaches to identify receptors involved in the guidance of trigeminal sensory axons during development, addressing the genesis of the three divisions of the trigeminal nerve, discrete projects in the maxillary distribution, and divergence of projections for large- and small-diameter sensory nerve fibers. This work should identify genes controlling neural sprouting and regeneration, processes thought to underlie the development and maintenance of chronic pain syndromes. Dr. Jon Levine will investigate mechanisms underlying neuropathic pain induced by chemotherapeutic agents that disrupt microtubules. Behavioral and electrophysiological experiments will elucidate the effect of the cytoskeletal disruption on nerve fiber activity, specific transduction molecules and ion channels, and second messenger systems. This work has the potential to identify specific cellular targets for novel pharmacological strategies to treat neuropathic pain paresthesias, arthralgias and myalgias induced by chemotherapy, and potentially to alleviate similar orofacial pain symptoms. The multi-disciplinary approach employed in this program project as a whole should provide information significantly increasing our understanding of trigeminal pain syndromes and thereby provide insights for the development of effective therapeutic interventions.